Induction of Cytoprotective Genes Through Nrf2 / Antioxidant Response Element Pathway: A New Therapeutic Approach for the Treatment of Inflammatory Diseases

In the last decade, it has become recognized that reactive oxygen species (ROS) play important roles in the multiple biological processes involved in the pathophysiology of chronic inflammation such as cell proliferation, adhesion molecule expression, cytokine and chemoattractant production and matrix metalloproteinase generation. Intracellular redox homeostasis is maintained by balancing the production of ROS with their removal through cellular antioxidant defense systems. The antioxidant response element (ARE) is a cis-acting DNA regulatory element located in the regulatory regions of multiple genes including phase II detoxification enzymes as well as antioxidant proteins including glutathione-S-transferases, NAD(P)H:quinone oxidoreductase-1, gamma-glutamylcysteine synthase, ferritin, and heme oxygenase-1. Nrf2 is the primary transcription factor that binds to the ARE, and through heterodimerization with other leucine-zipper containing transcription factors, activates the expression of these genes. It is evident that activation of ARE-regulated genes contributes to the regulation of cellular antioxidant defense systems. More importantly, there is a growing body of evidence suggesting that modulation of these cytoprotective genes has profound effects on immune and inflammatory responses. Activation of cytoprotective Nrf2/ARE-regulated genes can suppress inflammatory responses, whereas decreased expression of these genes results in autoimmune disease and enhanced inflammatory responses to oxidant insults. Thus, coordinate induction of cytoprotective genes through Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of immune and inflammatory diseases.